Project Summary/Abstract Epidermolysis Bullosa (EB) is a rare genetic skin disorder that causes extreme skin fragility leading to recurrent blister formations or erosions in response to little or no apparent trauma. People born with this disease have defective or lack the anchoring filaments that facilitate the adhesion of the epidermis, the outer layer of the skin to the inner dermal layers of the skin. Any skin trauma that creates friction between the skin layers results in painful blister formation and open wounds. Mild form of the disease may be limited to the hands and feet and the severe forms can affect generalized areas of the skin resulting in deformities and disability. The condition is also associated with significant pain and pruritus in most patients. More severe forms of EB are often lethal during childhood, typically because of overwhelming infection. Those who survive into adulthood are at high risk of developing squamous cell carcinomas, which can prove fatal. There are three main types of inherited EB (Simplex, Dystrophic, and Junctional) and, based on the type, the symptoms can range from mild to disabling or life threatening. EB is estimated to affect 20,000 to 50,000 people in the United States, mostly children and is acknowledged as an orphan disease by the U.S. Food and Drug Administration (FDA) . There is currently no cure or effective treatment; care is supportive and palliative. Better treatments producing clinically significant benefits are desperately needed for this serious disease. Scioderm, INC. is developing SD-101 (proprietary cream formulation containing various concentrations of allantoin) for EB. Scioderm has an open Investigational New Drug Application (IND 107,480) for SD-101 dermal cream (containing allantoin at 3% (SD-101-3.0), 6% (SD-101-6.0), and 9% (SD-101-9.0)). In this grant application, Scioderm is proposing to conduct a confirmatory multi-center, randomized, double-blind, and vehicle controlled Phase 3 study to assess the effectiveness, safety and clinical utility of SD-101-6.0 cream in subjects with EB. The proposed indication is closure of chronic wounds associated with patients with EB. SD- 101 will also be indicated for reduction of skin blistering and erosions associated with EB, by facilitating healing of skin lesions and reducing the incidence and/ or severity of new lesions. We expect SD-101 to be clinically safe and effective based on results obtained from three clinical studies: (1) a compassionate use study involving 44 EB patients using SD-101-1.5 (containing 1.5% allantoin), (2) an open-label FDA approved study in 8 pediatric EB patients using SD-101-3.0, and (3) a Phase 2B, multi- center, randomized, double-blind, vehicle controlled dose-selection study (SD-003) in 48 EB patients using either SD-101-6.0, SD-101-3.0, or SD-101-0.0 (placebo). The compassionate use study showed a reduction in coverage of blisters and lesions. In the open-label Phase 2 study with SD-101-3.0, complete closure of chronic target lesions was seen in the majority of patients within the first month (88%). SD-101-3.0 was also shown to significantly reduce body surface area (BSA) coverage of blisters and lesions across all EB subtypes. SD-101- 3.0 usage was also shown to have the potential to improve both pain and pruritus. In the Phase 2B study, SD- 101-6.0 was determined be the most efficacious dose in terms of complete closure of chronic target lesions EB patients. Lastly, a recently completed Phase 1 double blinded, parallel, vehicle-controlled study local tolerance study with SD-101-3.0, SD-101-6.0, and SD-101-9.0 revealed that the cream is well tolerated at all doses. For effective topical, locally delivered pharmaceutical products, both the active ingredient and the formulation are equally important. Scioderm has developed an innovative proprietary formulation containing allantoin which overcomes the low solubility of allantoin at neutral pH and its intrinsic instability. This formulation allows the emulsification and stability of allantoin at concentrations up to 9%, whereas allantoin is usually pharmaceutically unstable at concentrations above 0.5%. In addition, a suitable formulation was developed that allows allantoin to be delivered across various skin barriers in a dose related manner, without systemic absorption. Allantoin in SD-101 has demonstrated stability for over three years at room temperature, whereas in the absence of this stabilization, a viable shelf-life of less than a few months is achievable. Allantoin has been designated as an orphan product (designation 01-1510). SD-101 has also received breakthrough therapy (BT) designation by the FDA for the treatment of patients with inherited EB, which may enable expedited development and approval of SD-101 for EB patients. In addition, the Dermatology division of FDA has agreed to waive the majority of the long-term toxicology studies, including carcinogenicity and reproductive studies. All non-clinical studies have been completed to support registration. Agreement with the division was also reached regarding the study design for the pivotal program, including the definition of the primary endpoint. Lastly, the size of the safety database needed to support registration has also been agreed with the Division. This grant will be used to assist in the completion of the pivotal clinical program necessary for registration and approval of SD-101 for the treatment of skin effects across the various types of EB.